Project Summary (Project 2) The overarching goal of this project is to study key features of epigenetic circuitry in MM, with the objective of improving our understanding of global gene regulation in this cancer, and with the goal of deploying novel therapeutics that target key epigenomic circuits in MM as dependencies. Cells and cell states can be defined by their gene expression programs, and tumor cells commonly have deregulated gene expression programs. The production of a gene expression program is accomplished by the cell?s epigenetic apparatus. It is now possible, for any normal or cancer cell type, to identify the master transcription factors, the enhancer elements they occupy, and the genes they regulate, and thus to develop a testable model of this genome-wide epigenetic circuitry. Furthermore, it is possible to identify the gene regulatory elements on which the cell is most dependent, and thus identify the portions of the circuitry on which a cancer cell is most dependent. Tumor cells tend to develop striking dependencies on super-enhancer regulatory elements (3-6). Recent studies suggest that the transcriptional cofactors BRD4, CDK7 and CDK12 play especially important roles in tumor cell epigenetic circuitry, and their inhibition with small molecules can cause a loss of super-enhancer domains that drive genes with prominent roles in tumorigenesis (3-6). We propose to decipher the key features of MM epigenetic circuitry, to identify the features that confer great dependency, and to investigate the potential of small molecule inhibitors to disrupt those dependencies in MM. To accomplish these goals, the specific aims of the proposal are 1) To discover key features of epigenomic circuitry in multiple myeloma by integrated epigenomic analysis, 2) to determine epigenetic dependencies in multiple myeloma using gene editing approaches, and 3) to explore the ability of small molecule inhibitors of transcriptional cofactors to disrupt key nodes in multiple myeloma epigenetic circuitry.